Psilocybin produces amplified acute responses and sex-specific long-term increases in sensorimotor gating in the mGlu5 knockout mouse model of schizophrenia

In a mouse model of schizophrenia lacking the metabotropic glutamate receptor 5 (mGlu5), psilocybin (1 mg/kg) caused hyperlocomotion, while normal mice showed no such effect. Male knockout mice also had a stronger head-twitch response, indicating enhanced serotonin 2A receptor signaling. Psilocybin increased neural activity in the claustrum of normal but not knockout mice, showing that intact mGlu5 signaling is needed for this effect. Psilocybin did not change anxiety-like behavior but increased immobility in a stress test. Notably, it produced a sustained normalization of sensorimotor gating in female knockout mice nine days after treatment, suggesting sex-dependent long-term effects.

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Abstract

Abstract Psilocybin is a serotonergic psychedelic drug with emerging therapeutic applications, yet its actions under glutamatergic dysfunction, and relevance to schizophrenia and associated psychiatric disorders, remain unclear. We examined the acute and long-lasting effects of psilocybin (1 mg/kg, intraperitoneal) on behavioral and neural outcomes in the metabotropic glutamate receptor 5 (mGlu5) knockout (KO) mouse model of schizophrenia. The mGlu5 KO mice displayed psilocybin-induced hyperlocomotion, whereas wild-type (WT) mice did not. Additionally, male mGlu5 KO mice showed an amplified psilocybin-induced head-twitch response (HTR) compared with WT males, consistent with sex-dependent enhancement of 5-HT 2A receptor-mediated signaling. Acute psilocybin increased c-Fos expression in the claustrum of WT but not KO mice, suggesting intact mGlu5 signaling is required for psilocybin-evoked claustral recruitment. Psilocybin did not alter anxiety-like behavior in the light–dark box and increased immobility time in the Porsolt test. Strikingly, psilocybin produced a sustained normalization in prepulse inhibition (a measure of sensorimotor gating) in female KO mice, evident nine days after treatment. Together, these findings indicate that disrupted mGlu5 signaling amplifies acute responses to psilocybin and reveals a sex-dependent long-term effect on sensorimotor gating. These results refine understanding of glutamatergic–serotonergic interactions and motivate further work evaluating psilocybin across schizophrenia-relevant endophenotypes.